Year : 2013  |  Volume : 16  |  Issue : 3  |  Page : 180--185

Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: A randomized, double-blind placebo controlled trial

Shreedhar S Joshi, AM Jagadeesh 
 Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, Karnataka, India

Correspondence Address:
Shreedhar S Joshi
Department of Cardiac Anesthesiology, Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bannerghatta Road, Bangalore - 560 069, Karnataka


Aims and Objectives: We evaluated the efficacy of perioperative pregabalin on acute and chronic post-operative pain after off-pump coronary artery bypass (OPCAB) surgery. Materials and Methods: Forty patients undergoing elective OPCAB surgery were randomized to pregabalin and control groups. Pregabalin group received 150 mg pregabalin 2 h prior to induction of anesthesia and 75 mg twice daily for 2 post-operative days whereas the control group received placebo at similar timings; pregabalin and placebo were administered by an anesthesiologist blinded to the drugs. Pain scores (visual analogue scale [VAS]) and sedation scores were observed at 0, 4, 6, 12, 24, 36 and 48 h after extubation. Time to extubation, tramadol consumption and side-effects were noted. VAS score was analyzed by Mann-Whitney U test. The analysis of variance test for repeated measures was used for comparison of the means of continuous variables. Group comparisons were made using the Chi-square-test. Results: Pain-scores at 6, 12, 24 and 36 h from extubation at rest and at deep breath were less in pregabalin treated patients ( P < 0.05). Tramadol consumption was reduced by 60% in pregabalin group ( P < 0.001). Extent of sedation, extubation times and incidence of nausea were comparable. The effect on chronic post-operative pain was not significant. Conclusions: Perioperative pregabalin reduced pain scores at rest and deep breath and reduced consumption of tramadol in the post-operative period without delaying extubation and causing excessive sedation.

How to cite this article:
Joshi SS, Jagadeesh A M. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: A randomized, double-blind placebo controlled trial.Ann Card Anaesth 2013;16:180-185

How to cite this URL:
Joshi SS, Jagadeesh A M. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: A randomized, double-blind placebo controlled trial. Ann Card Anaesth [serial online] 2013 [cited 2021 Jan 23 ];16:180-185
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Optimal dynamic pain management has become a pre-requisite for early post-operative recovery. [1] Poor pain management during the early post-operative period has deleterious effects on pulmonary (atelectasis, pneumonia, bronchial secretion stasis), cardiovascular (increased oxygen consumption, tachycardia), and musculoskeletal (muscle weakness and disuse) systems and induces stress responses and hyperglycemia. [2] The incidence of chronic post-cardiac surgical pain (PCP) is estimated to be 11%, making it an important health care issue after cardiac surgery. [3] The aim of analgesic protocols is to reduce pain intensity, decrease side-effects of analgesic agents and to improve patient comfort. The American Society of Anesthesiologists task force on management for acute post-operative pain recommends the use of multimodal techniques of pain management. These include regional-epidural analgesia; opioids and around the clock regimen of non-steroidal anti-inflammatory drugs, cyclooxygenase inhibitors, or acetaminophen. The regimens should be tailored to individual patients. [4] Epidural analgesia during cardiac surgeries is known to reduce pulmonary complications and perioperative myocardial ischemic events, but these benefits might be outweighed by the risk of epidural hematoma and subsequent neurological consequences in anti-coagulated patients. [5] Opioids can cause nausea, vomiting, pruritus, and respiratory depression when they are used solely for analgesia. Recently anticonvulsants such as gabapentin and pregabalin have been used to supplement opioids in cardiac surgery. During off-pump coronary artery bypass surgery (OPCAB), fast tracking has become common. One of the rationales for fast tracking patients is that it permits patients to ambulate early and cough soon after surgery, both of which reduce pulmonary complications. Robust pain management is essential for fast tracking. Inadequate pain relief prolongs mechanical ventilation, promotes atelectasis and reduces oxygenation and increases oxygen demand and perioperative ischemic events. All of these factors have the potential to negate the advantages of avoiding cardiopulmonary bypass.

Pregabalin acts by decreasing dorsal horn neuron hyper-excitability that is induced by tissue damage. It also attenuates central sensitization due to peripheral stimuli as evidenced by hyperalgesic experiment in human volunteers. [6] Pregabalin is a gamma-amino butyric acid analogue with analgesic, anticonvulsant and anxiolytic effects. It is more potent than its congener gabapentin. It has 90% bioavailability after oral administration and its peak plasma concentration is achieved 30 min to 2 h after single oral dose. At that time, the concentration of pregabalin in the brain is sufficient to provide anti-hyperalgesic effects. [7] The drug binds to alpha-2-delta subunits of voltage-dependent calcium channels located on pre-synaptic neuron sites. The alteration of calcium currents modulates the release of various neurotransmitters, such as glutamine and substance P and restores hyperactive neurons to a normal state. Common side effects include somnolence, which is seen in up to 30% cases, and dizziness. No overt cardiovascular effects are known. [8] This study protocol was designed to evaluate the efficacy of perioperative pregabalin on reducing acute and chronic post-operative pain and opioid consumption in OPCAB surgeries. Our secondary outcome was to observe the sedative effects of pregabalin at the dosage used in this study.

 Materials and Methods

After Institutional Review Board approval and obtaining written informed consent, the participating patients were randomized into two groups (Pregabalin and Control group). Randomization was conducted using the closed-envelope-method. In this double-blind, randomized, placebo-control design, patients in the pregabalin group received 150 mg pregabalin capsules (LYRICA ® , Pfizer Inc., Germany.), and the control group received placebo (similar looking sucrose containing capsules prepared by the hospital pharmacy) 2 h before induction of anesthesia. Pregabalin capsules (75 mg) were given every 12 h for 2 post-operative days to the pregabalin group, and the control group received placebo capsules at same times. The study drug or placebo was administered by an anesthesiologist who was not involved in the study. Patients of either sex scheduled for primary OPCAB, aging 30-65 years were included in the study. Patients with pre-operative unstable hemodynamic, intra-aortic-balloon-pump, inotropes, congestive cardiac failure, left ventricular dysfunction (ejection fraction < 40%), renal or hepatic dysfunction, on anticonvulsants, anti-depressants, or chronic analgesic use were excluded. After random allocation to either group on a pre-operative visit, consenting patients were instructed in the use of visual analogue scale (VAS) for pain at rest (VAS rest) and during deep breathing (VAS deep breath) with 0: indicating no pain, and 10 indicating worst pain imaginable) and incentive spirometry.

Patients were pre-medicated with tab diazepam 10 mg night before and on the morning of surgery. All cardiac medications except angiotensin converting enzyme inhibitors were continued till the morning of surgery. After establishing standard hemodynamic monitoring (electrocardiogram and pulse oximeter oxygen saturation), radial artery was cannulated under local anesthesia. Anesthesia was induced with fentanyl 2-4 μg/kg, midazolam 0.05 mg/kg and propofol 0.5-1.5 mg/kg, endotracheal intubation was facilitated with vecuronium 0.1 mg/kg. Anesthesia was maintained with isoflurane (end-tidal concentration 0.8-1.5%), fentanyl infusion of 2-4 μg/kg/h and intermittent doses of vecuronium as clinically indicated. In the post-operative period, propofol infusion 100-200 μg/kg/h was maintained for two hours. At the start of weaning from mechanical ventilation, propofol infusion was stopped and intravenous paracetamol 1 gm was administered slowly. Criteria for weaning from mechanical ventilation were- hemodynamic stability, absence of significant rhythm disturbances, bleeding < 10 ml/kg/h, warm peripheries, PO 2 > 100 mmHg at FiO 2 < 0.4, PCO 2 < 40 mmHg on support modes of ventilation, tidal volume 5-10 ml/kg, and respiratory rate 15-20/min. Patients were extubated once they fulfilled the criteria. Patients were interrogated for pain by VAS scoring system at rest and during deep breathing by an intensivist blinded to the study groups at 0 h (at extubation), thereafter at 4, 6, 12, 24, 36, and 48 h from extubation. Paracetamol 1 gm was administered 6 th hourly to all patients. Break-through pain was defined as VAS ≥ 4 either at rest or during deep breathing, and rescue analgesic tramadol 1 mg/kg was administered. Second rescue analgesic planned was intravenous diclofenac 75 mg if VAS persistently remained > 4 after tramadol administration. Dynamic pain was defined as the difference in VAS scores between rest and deep breath of > 2 points. Pain was classified into mild, moderate and severe for analysis (mild VAS 0-4, moderate VAS 5-7, severe VAS > 8). Chronic pain was assessed at 1 month and 3 months after discharge by telephonic interview by an anesthesiologist who was not a part of the perioperative management of the enrolled patients. Time to extubation, hemodynamic parameters, inotrope score, [9] and number of balls-raised during incentive spirometry [10] (as an indicator of inspiratory flow rate) and episodes of break-through pain till 48 h were noted. Richmond agitation sedation scoring (RASS) was used to assess sedation at similar intervals. [11] The scoring was defined as combative +4; very agitated +3; agitated +2; restless +1; 0 alert and calm; drowsy - 1; light sedation - 2; moderate sedation - 3; deep sedation - 4; and unarousable as - 5). Respiratory depression was defined as respiratory rate < 10/min, oxygen saturation < 90-92%, PCO 2 > 45 mmHg. If patients experienced nausea or vomiting, they were treated with intravenous ondansetron 4 mg. A sample size of 16 in each group was sufficient to detect a clinically important difference of 1 point on the VAS pain scores, assuming a standard deviation of 1.3, using a two-tailed t-test of difference between means, with a power of 80%, and a significance level of 5%. This number was increased to 20 for each group to make up for a predicted drop-out from follow up of 25%. VAS score being a nonparametric data was analyzed by Mann-Whitney U test. The two-way analyses of variance test for repeated measures was used for comparison of the means of continuous variables. Categorical variables are given as counts, and group comparisons were made using the Chi-square-test. All calculations were performed using SPSS version 14 (SPSS Inc., Chicago, IL) for Windows. The continuous variables are presented as mean with SD and categorical variables as median with interquartile range. A P value of < 0.05 was considered to indicate statistical significance.


All the forty patients completed the study protocol. The groups were comparable in terms of demographic and intraoperative clinical characteristics [Table 1].{Table 1}

The VAS scores at rest [Figure 1] and during deep breath [Figure 2] at extubation (0 h), and at 4, 6, 12, 24, 36 and 48 h from extubation are depicted graphically. Pain scores at rest were less in pregabalin treated patients at 6, 12, 24 and 36 h from extubation (P < 0.05). Pain scores at deep breath were less in pregabalin group than control but with statistical significance at 4, 6, 12, 24 and 36 h from extubation (P < 0.05). Pain characteristics are described in [Table 2]. Tramadol consumption was reduced by 60% in pregabalin group as compared to control patients (P < 0.001). Patients without a need for rescue analgesic were more in pregabalin group. Break-through episodes were more in the control group as compared to pregabalin treated group (P < 0.05). This difference was more obvious in the first 24 h. Dynamic pain was observed in more number of patients in the control group in comparison to pregabalin treated group (P < 0.05) at 4 h from extubation. Pain at rest and deep breathing at 1 month and 3 months after surgery were comparable among the groups [Figure 3]. Heart rate and mean arterial pressure were lower in pregabalin treated patients than their controls without any statistical difference (P > 0.05). RASS scores and vomiting were comparable in both groups [Table 3]. Respiratory depression was not observed in any patients [Table 3]. Extubation time (447 ± 117 vs. 461 ± 119; P = 0.7), inotrope score (3.6 ± 4.0 vs. 2.4 ± 3.2; P = 0.3), intensive care unit stay (3.05 ± 0.68 vs. 3.2 ± 1.77; P = 0.59) and hospital stay (8.6 ± 1.35 vs. 9.5 ± 0.41; P = 0.2) were comparable between groups. Peak inspiratory flow rates as assessed by incentive spirometry were higher in pregabalin group as compared to control group at 12, 24 and 36 h from extubation (P < 0.05). The pain severity scores [Figure 4] were higher in the control group as compared to pregabalin group at 12, 24 and 36 h (P < 0.05).{Table 2}{Table 3}{Figure 1}{Figure 2}{Figure 3}{Figure 4}


The primary finding of the study is reduced pain scores and resultant reduction in opioid consumption in pregabalin treated patients in early post-operative period. Chronic pain at 1 month and 3 months was less incident in both the groups without any significant difference. Dynamic pain as assessed by the difference in VAS scores during deep breathing was less in pregabalin patients. Pregabalin group had lower grades of pain as compared to the control group. Sedation was comparable and respiratory depression was not observed in any patients. Nausea and vomiting were observed in both groups without any statistical difference. The lesser pain lead to improved lung functions as assessed by incentive spirometry.

Varying dosages of pregabalin in the perioperative period have been used for analgesic effects. Up to 36% incidence of sedation, somnolence and dizziness has been reported. It has also been suggested to use lower doses of pregabalin to minimize such side effects, and hopefully, maintaining therapeutic effects. [12] We designed our study with the intent to prevent spinal cord sensitization by pre-operative administration of 150 mg of pregabalin that was continued for 2 days after surgery (75 mg twice daily for 2 days). We planned to use the drug for 48 h as after this period patients are transferred to low dependency units and adverse event monitoring can be compromised. As the effect of extracorporeal circulation on plasma concentrations of pregabalin is not well known, the OPCAB patients is an ideal cohort to study the effect as they avoid this problem. [13] Pesonen et al., [14] used pregabalin 150 mg before surgery and 75 mg twice a day for 5 days and reported a reduction in opioid consumption by 44% at 24 h and 48% by 5 th post-operative day. Sedation scores on RASS were not significantly different in comparison to the placebo group. Similar to the results of Pesonen et al., we also observed a 60% reduction in tramadol consumption in pregabalin treated group. The time to extubation was longer in their cohort, but in our study, time to extubation was comparable to the control patients. This difference could be because of our anesthetic technique targeting an early extubation.

A meta-analysis on efficacy of pregabalin in acute post-operative pain concluded that pregabalin reduced opioid consumption and attendant side effects. Most of the surgeries in the meta-analysis were superficial with low grade pain scores, which could be a confounding factor to correlate to the present study. Cardiac surgical patients have moderate to severe grade pain after the procedure. The pain on movement and deep breathing has a significant bearing on the recovery process. The present study has observed a difference in pain at deep breathing from the control group till 48 h, with statistical significance at 4 h from extubation. [15]

The incidence of PCP, in the recent past, is reported to be at 11-24% as compared to earlier retrospective studies reporting 18-61%. [16],[17],[18] In our study chronic pain at 1 month and 3 months was less and comparable in both the group. Studies assessing chronic pain after cardiac surgery have enrolled large cohort as the incidence is less compared to retrospective older analysis. Most of these patients developing chronic pain have mild to moderate pain and less than 3% have severe pain. One of the high-risk factors for development of chronic pain after cardiac surgery is the severity of pain in acute post-operative period. [3] In the present study, we observed most patients in pregabalin group having mild to moderate pain as compared to control group in whom most patients had moderate to severe pain. This difference was statistically significant at 12, 24, and 36 h from extubation. Pregabalin by reducing the severity of acute post-operative pain can reduce the occurrence of chronic pain after cardiac surgery. The incidence of sedation and somnolence are known to be significant with pregabalin usage, and cautionary advice has been suggested. In the present study, the occurrence of sedation as assessed by RAAS scoring was comparable in both groups. There were no episodes of respiratory depression requiring intervention. Except for one episode of moderate sedation (RASS of - 3), most patients in pregabalin group had a RAAS score of - 1 (not fully alert, but has sustained awakening (eye-opening/eye contact) to voice for > 10 s). All the patients co-operated during physiotherapy. The inspiratory flow rate assessed by the number of balls raised at incentive spirometry was always higher compared to the control group (statistically significant at 6, 12, and 24 h from extubation). This gives a clinical impression of better dynamic pain control with pregabalin. Pregabalin provided calm and comfortable patients, who were easily arousable, and had better lung dynamic function.

Nausea and vomiting are associated side effects of opioids, but the reduction of opioid consumption with pregabalin resulted in reduced nausea and vomiting. In the present study the incidence was low in both groups. Few case series have cautioned on the deterioration of chronic heart failure with pregabalin. [19],[20],[21] In the present study, we excluded patients who were in NYHA class III and had a history of congestive heart failure in the past.

The present study has a few practical limitations. The power of the study was analyzed for a difference in acute post-operative pain as evaluated by VAS scores. A larger cohort is necessary to assess the effects on chronic pain, nausea and vomiting. Additionally, we should have assessed the effect of improved pain control on pulmonary outcome by objective pulmonary function tests.

In conclusion, perioperative pregabalin for OPCAB surgery reduced pain scores; the patients had opioid sparing effect without significant sedation or respiratory depression. Pregabalin-treated patients had lesser pain on deep breathing in the post-operative period. Although, there was no difference in chronic pain characteristics, the reduction of pain severity in acute post-operative period might reduce the incidence of chronic pain. A larger cohort study is required to assess its effects on the incidence of chronic pain in OPCAB surgery.


We would like to thank our colleagues in Department of Cardiac Anesthesiology, Surgery and Cardiac care nursing for their support in data acquisition. we thank Dr. Deepak Borde for being an inspiration and for editing the manuscript.


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